RU2009125024A

RU2009125024A - Compounds of Substituted Diazepanes as Antagonists of Orexin Receptors

Info

Publication number: RU2009125024A
Application number: RU2009125024/04A
Authority: RU
Inventors: Джеффри М. БЕРГМАН (US); Джеффри М. Бергман; Майкл Дж. БРЕСЛИН (US); Майкл Дж. БРЕСЛИН; Пол Дж. КОУЛМАН (US); Пол Дж. Коулман; Кристофер Д. КОКС (US); Кристофер Д. КОКС; Свати П. МЕРСЕР (US); Свати П. Мерсер; Энтони Дж. РОКЕР (US); Энтони Дж. Рокер
Original assignee: Мерк Шарп Энд Домэ Корп. (Us); Мерк Шарп Энд Домэ Корп.
Priority date: 2006-12-01
Filing date: 2007-11-30
Publication date: 2011-01-10
Also published as: SV2009003276A; EP2392572A1; US20080132490A1; AR063979A1; MY161834A; RU2010150818A; NO20092470L; JP2011079848A; MA31016B1; AU2010249269A1; KR101217057B1; CA2670892C; JP2010511621A; CO6190524A2; ES2397188T3; CN101880276A; CA2670892A1; RS52617B; KR20100031767A; CY1113798T1

Abstract

1. Соединение формулы I: ! ! где R1 является фенилом, замещенным R1a, R1b и R1c; ! R2 является гетероарилом, замещенным R2a, R2b и R2c; ! R1a, R1b, R1c, R2a, R2b и R2c независимо выбирают из группы, состоящей из ! (1) водорода, ! (2) галогена, ! (3) гидроксила, ! (4) -(С=О)m-On-C1-6алкила, где m равно 0 или 1, n равно 0 или 1 (где, если m равно 0 или n равно 0, то присутствует связь), где соседние R2a и R2b или R2b и R2c могут быть соединены вместе, с образованием циклоалкильного или циклоалкокси кольца, и где алкил является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (5) -(С=О)m-On-C3-6циклоалкила, где циклоалкил является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (6) -(С=О)m-C2-4алкенила, где алкенил является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (7) -(С=О)m-C2-4алкинила, где алкинил является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (8) -(С=О)m-On-фенила или -(С=О)m-On-нафтила, где фенил или нафтил является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (9) -(С=О)m-On-гетероцикла, где гетероцикл является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (10) -(С=О)m-NR10R11, где R10 и R11 независимо выбирают из группы, состоящей из ! (а) водорода, ! (b) С1-6алкила, который является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (с) С3-6алкенила, который является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (d) циклоалкила, который является незамещенным или замещен одним или несколькими заместителями, выбранными из R13, ! (е) фенила, � 1. The compound of formula I:! ! where R1 is phenyl substituted with R1a, R1b and R1c; ! R2 is heteroaryl substituted with R2a, R2b and R2c; ! R1a, R1b, R1c, R2a, R2b and R2c are independently selected from the group consisting of! (1) hydrogen,! (2) halogen,! (3) hydroxyl! (4) - (C = O) m-On-C1-6 alkyl, where m is 0 or 1, n is 0 or 1 (where, if m is 0 or n is 0, then there is a bond), where adjacent R2a and R2b or R2b and R2c may be joined together to form a cycloalkyl or cycloalkoxy ring, and wherein the alkyl is unsubstituted or substituted with one or more substituents selected from R13,! (5) - (C = O) m-On-C3-6 cycloalkyl, where cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,! (6) - (C = O) m-C2-4 alkenyl, where alkenyl is unsubstituted or substituted by one or more substituents selected from R13,! (7) - (C = O) m-C2-4 alkynyl, where alkynyl is unsubstituted or substituted with one or more substituents selected from R13,! (8) - (C = O) m-On-phenyl or - (C = O) m-On-naphthyl, where phenyl or naphthyl is unsubstituted or is substituted by one or more substituents selected from R13,! (9) - (C = O) m-On-heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R13,! (10) - (C = O) m-NR10R11, where R10 and R11 are independently selected from the group consisting of! (a) hydrogen,! (b) C1-6 alkyl, which is unsubstituted or substituted by one or more substituents selected from R13,! (c) C3-6 alkenyl, which is unsubstituted or substituted by one or more substituents selected from R13,! (d) cycloalkyl which is unsubstituted or substituted by one or more substituents selected from R13,! (f) phenyl, �

Claims

1. The compound of formula I:

where R ¹ is phenyl substituted with R ^1a , R ^1b and R ^1c ;

R ² is heteroaryl substituted with R ^2a , R ^2b and R ^2c ;

R ^1a , R ^1b , R ^1c , R ^2a , R ^2b and R ^{2c are} independently selected from the group consisting of

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) - (C = O) _m —O _n —C _1-6 alkyl, where m is 0 or 1, n is 0 or 1 (where, if m is 0 or n is 0, then there is a bond), where adjacent R ^2a and R ^2b or R ^2b and R ^2c may be joined together to form a cycloalkyl or cycloalkoxy ring, and wherein the alkyl is unsubstituted or substituted with one or more substituents selected from R ¹³ ,

(5) - (C = O) _m —O _n —C _3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one or more substituents selected from R ¹³ ,

(6) - (C = O) _m -C _2-4 alkenyl, where alkenyl is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(7) - (C = O) _m —C _2-4 alkynyl, wherein the alkynyl is unsubstituted or substituted with one or more substituents selected from R ¹³ ,

(8) - (C = O) _m -O _n- phenyl or - (C = O) _m -O _n- naphthyl, where phenyl or naphthyl is unsubstituted or is substituted by one or more substituents selected from R ¹³ ,

(9) - (C = O) _m —O _n -heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(10) - (C = O) _m —NR ¹⁰ R ¹¹ where R ¹⁰ and R ^{11 are} independently selected from the group consisting of

(a) hydrogen,

(b) C _1-6 alkyl, which is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(c) C _3-6 alkenyl, which is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(d) cycloalkyl, which is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(e) phenyl which is unsubstituted or substituted by one or more substituents selected from R ¹³ and

(f) a heterocycle which is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(11) -S (O) ₂ -NR ¹⁰ R ¹¹ ,

(12) —S (O) _q —R ¹² , where q is 0, 1, or 2, and where R ^{12 is} selected from the group of definitions for R ¹⁰ and R ¹¹ ,

(13) —CO ₂ N,

(14) -CN,

(15) -NO ₂ ,

(16) = O and

(17) -B (OH) ₂ ,

with the proviso that at least one of R ^2a , R ^2b or R ^2c is halogen or C _1-6 alkyl, or where adjacent R ^2a and R ^2b or R ^2b and R ^2c can be joined together to form a cycloalkyl or cycloalkoxy ring where alkyl, cycloalkyl or cycloalkoxy is unsubstituted or substituted by one or more substituents selected from R ¹³ ;

R ³ is —C _1-6 alkyl or —C _3-6 cycloalkyl which are unsubstituted or substituted by one or more substituents selected from R ¹³ ;

R ^{13 is} selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) - (C = O) _m —O _n —C _1-6 alkyl, wherein the alkyl is unsubstituted or substituted with one or more substituents selected from R ¹⁴ ,

(4) -O _n - (C _1-3 ) perfluoroalkyl,

(5) - (C = O) _m —O _n —C _3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one or more substituents selected from R ¹⁴ ,

(6) - (C = O) _m -C _2-4 alkenyl, where alkenyl is unsubstituted or substituted by one or more substituents selected from R ¹⁴ ,

(7) - (C = O) _m -O _n- phenyl or - (C = O) _m -O _n- naphthyl, where phenyl or naphthyl is unsubstituted or is substituted by one or more substituents selected from R ¹⁴ ,

(8) - (C = O) _m —O _n -heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R ¹⁴ ,

(9) - (C = O) _m -NR ¹⁰ R ¹¹ ,

(10) -S (O) ₂ -NR ¹⁰ R ¹¹ ,

(11) -S (O) _q -R ¹² ,

(12) —CO ₂ N,

(13) -CN,

(14) = 0 and

(15) -NO ₂ ;

R ¹⁴ selected from the group consisting of

(1) hydroxyl,

(2) halogen,

(3) C _1-6 alkyl,

(4) -C _3-6 cycloalkyl,

(5) —O — C _1-6 alkyl,

(6) —O (C = O) —C _1-6 alkyl,

(7) -NH-C _1-6 alkyl,

(8) phenyl,

(9) heterocycle,

(10) —CO ₂ N and

(11) -CN;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 of formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 of formula Ie:

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, where R ¹ represents phenyl, which is unsubstituted or substituted by one or more substituents selected from

(1) halogen,

(2) hydroxyl,

(3) —O _n —C _1-6 alkyl, where n is 0 or 1 (where if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R ¹³ _,

(4) -O _n- phenyl, where phenyl is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(5) -heterocycle, where the heterocycle is unsubstituted or substituted by one or more substituents selected from R ¹³ ,

(6) -NR ¹⁰ R ¹¹ where R ¹⁰ and R ^{11 are} independently selected from the group consisting of

(a) hydrogen,

(7) -S (O) ₂ -NR ¹⁰ R ¹¹ ,

(8) —CO ₂ N,

(9) -CN,

(10) -NO ₂ and

(11) -B (OH) ₂ .

5. The compound according to claim 4, where R ¹ represents phenyl, which is unsubstituted or substituted by one or more substituents selected from methyl, —CF ₃ , halogen, —OCF ₃ , —OCH ₃ , —OCH ₂ CH ₃ , - CO ₂ CH ₃ , —CN, —N (CH ₃ ), —NH (CH ₂ CH ₃ ), —NO ₂ , —B (OH) ₂ , triazolyl, or phenyl.

6. The compound according to claim 5, where R ¹ represents phenyl, which is unsubstituted or substituted by one or more substituents selected from methyl or triazolyl.

7. The compound according to claim 1, where R ² represents heteroaryl, which is unsubstituted or substituted by one or more substituents selected from

(1) halogen,

(2) hydroxyl,

(3) —O _n —C _1-6 alkyl, where n is 0 or 1 (where if n is 0, then a bond is present), and where the alkyl is unsubstituted or substituted with one or more substituents selected from R ¹³ _,

(a) hydrogen,

(7) -S (O) ₂ -NR ¹⁰ R ¹¹ ,

(8) —CO ₂ N,

(9) -CN and

(10) -NO ₂ ,

with the proviso that at least one substituent is halogen or C _1-6 acyl or where two adjacent substituents are joined together to form a cycloalkyl ring.

8. The compound according to claim 7, where R ² selected from the group consisting of

(1) benzimidazolyl,

(2) benzothiazolyl,

(3) benzoxazolyl,

(4) cyclopentylpyrimidinyl,

(5) dihydrocyclopentapyrimidinyl,

(6) dihydroquinolinyl,

(7) furopyrimidinyl,

(8) pyrazolopyrimidinyl,

(9) pyridinyl,

(10) pyridopyrimidinyl,

(11) pyrimidinyl,

(12) quinazolinyl,

(13) quinolinyl,

(14) quinoxalinyl,

(15) tetrahydroquinazolinyl,

(16) thiadiazolyl and

(17) thienopyrimidinyl,

which are substituted with halogen or C _1-6 alkyl and optionally substituted with a hydroxyl group, —O — C _1-6 alkyl, keto, —NH _2, or phenyl.

9. The compound of claim 8, where R ² selected from the group consisting of

(1) 1,3-benzoxazol-2-yl,

(2) 2- (6,7-dihydro-5H-cyclopenta [d] pyrimidine) yl,

(3) 2- (7,8-dihydroquinolin-5 (6H) -one) yl,

(4) 2- (furo [2,3] pyrimidine) silt,

(5) 2- (pyrazolo [3,4] pyrimidine) yl,

(6) 2-pyridinyl,

(7) 2- (pyrido [2,3-d] pyrimidin-7 (8H) -one) yl,

(8) 2-pyrimidinyl,

(9) 2-quinazolinyl,

(10) 2-quinoxalinyl,

(11) 2- (5,6,7,8-tetrahydroquinazoline) sludge,

(12) 2- (thieno [2,3-d] pyrimidine) yl and

(13) 2- (thieno [2,3] pyrimidin-4-amine) yl,

which are substituted with methyl, chlorine or fluorine.

10. The compound according to claim 1, where one of R ^2a , R ^2b or R ^2c is halogen or C _1-6 alkyl and the other of R ^2a , R ^2b or R ^2c are hydrogen.

11. The compound according to claim 1, where R ³ represents-C _1-6 alkyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -C _1-6 alkyl,

(4) - (C _1-3 ) perfluoroalkyl,

(5) -O- (C _1-3 ) perfluoroalkyl,

(6) -C _3-6 cycloalkyl; and

(7) -C _2-4 alkenyl.

12. The compound of claim 11, wherein R ³ is —C _1-6 alkyl.

13. The compound according to claim 11, where R ³ is methyl.

14. A compound that is selected from the group consisting of

6-fluoro-2 - {(5R) -5-methyl-4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} quinazoline;

5-chloro-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- silt} -1,3-benzoxazole;

methyl-3 - {[(7R) -4- (5-chloro-1,3-benzoxazol-2-yl) -7-methyl-1,4-diazepan-1-yl] carbonyl} -4- (2H- 1,2,3-triazol-2-yl) benzoate;

3 - {[(7R) -4- (5-chloro-1,3-benzoxazol-2-yl) -7-methyl-1,4-diazepan-1-yl] carbonyl} -4- (2H-1, 2,3-triazol-2-yl) benzoic acid;

[3 - {[(7R) -4- (5-chloro-1,3-benzoxazol-2-yl) -7-methyl-1,4-diazepan-1-yl] carbonyl} -4- (2H-1 2,3-triazol-2-yl) phenyl] methanol;

6,7-difluoro-2 - {(5R) -5-methyl-4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} quinoxaline;

5-methyl-2 - {(5R) -5-methyl-4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} thieno [ 2,3-d] pyrimidine;

2 - {(5R) -5-methyl-4- [2- (2H-1,2,3-tyrazol-2-yl) benzoyl] -1,4-diazepan-1-yl} -5,6,7 8-tetrahydroquinazoline;

2 - {(5R) -5-methyl-4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} -6,7-dihydro -5H-cyclopenta [d] pyrimidine;

2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} -7 , 8-dihydroquinolin-5 (6H) -one;

6-chloro-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- yl} pyrido [2,3-d] pyrimidin-7 (8H) -one;

5-methyl-2- (4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} thieno [2,3] pyrimidin-4- amine;

5-methyl-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- il} furo [2,3] pyrimidine;

2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} -6 , 7-dihydro-5H-pyrano [2,3-d] pyrimidine;

(5R) -5-methyl-1- (5-methyl-4-propylpyrimidin-2-yl) -4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepane;

(5R) -1- [4-chloro-5- (trifluoromethyl) pyrimidin-2-yl] -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl ) benzoyl] -1,4-diazepane;

(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1- [4-methyl-5- (trifluoromethyl) pyrimidin-2 -yl] -1,4-diazepane;

(5R) -1- [4-methoxy-5- (trifluoromethyl) pyrimidin-2-yl] -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl ) benzoyl] -1,4-diazepane;

2-methyl-6 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- yl} pyridin-3-yl) methanol;

4-methyl-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- silt} -1,3-benzoxazole;

5-methyl-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- il} thieno [2,3-d] pyrimidine;

2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} -5 6,7,8-tetrahydroquinazoline;

2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1-yl} -6 , 7-dihydro-5H-cyclopenta [d] pyrimidine;

5,6-dimethyl-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan- 1-yl} furo [2,3-d] pyrimidine;

4-ethoxy-5,6-dimethyl-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1, 4-diazepan-1-yl} furo [2,3-d] pyrimidine;

1,3-dimethyl-6 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan- 1-yl} -1H-pyrazolo [3,4-d] pyrimidine;

5-bromo-2 - {(5R) -5-methyl-4- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,4-diazepan-1- silt} -1,3-benzoxazole;

(5R) -5-methyl-1- [4-methyl-5- (trifluoromethyl) pyrimidin-2-yl] -4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] - 1,4-diazepane;

(5R) -1- [4-methoxy-5- (trifluoromethyl) pyrimidin-2-yl] -5-methyl-4- [2- (2H-1,2,3-triazol-2-yl) benzoyl] - 1,4-diazepane;

or their pharmaceutically acceptable salts.

15. A pharmaceutical composition comprising an inert carrier and a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 or its pharmaceutically acceptable salt for use in medicine.

17. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of sleep disorders.

18. A method for improving sleep quality in mammalian patients in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

19. A method of treating insomnia in mammalian patients in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

20. A method of treating or controlling obesity in mammalian patients in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.